Sustained virologic response in DAA-treated HCV patients on anti-epileptic drugs
Authors: Sonalie Patel, Allison Moser, Hazel Domingo
Journal: Journal of Hepatology (2023)

Up to 85% of patients infected with chronic hepatitis C virus (HCV) are taking concomitant medications, and therefore, it is imperative that drug-drug interactions be considered before initiation of direct-acting antivirals (DAAs) for HCV treatment.[1]Gilead hepatitis C virus concomitant medications analysis. Internal claims data. December 2020Google Scholar The severity of drug-drug interactions between DAAs and certain anti-epileptic drugs (AEDs), such as carbamazepine, oxcarbazepine, phenobarbital, and phenytoin is labeled as “moderate” or “major” in common tertiary resources. In particular, co-administration of glecaprevir/pibrentasvir (GLE/PIB) and carbamazepine 200 mg twice daily led to glecaprevir CMAX and AUC reduction of 67% and 66% and of pibrentasvir CMAX and AUC reduction of 50% and 51%, respectively. Co-administration of sofosbuvir with carbamazepine 300 mg twice daily led to a 48% reduction of sofosbuvir CMAX and AUC, thereby raising concerns regarding diminished efficacy of DAAs and subsequent treatment failure. However, in light of recent real-world data, the University of Liverpool downgraded the interactions between DAAs and previously mentioned AEDs to “potential interactions.”[2]Hep drug interactions. University of Liverpool, April 2023Google Scholar Though a theoretical risk remains, the growing body of evidence suggests otherwise. Burger et al. described 11 patients who achieved sustained virologic response (SVR) with DAAs despite receiving concomitant AEDs: carbamazepine (n = 1), oxcarbazepine (n = 3), phenobarbital (n = 2), and phenytoin (n = 5).3Burger D. Aktas H. de Knegt R. Sustained virological response in an HCV-infected patient on an enzyme-inducing anti-epileptic agent despite undetectable trough plasma levels of velpatasvir.J Hepatol. 2023; 78: e175-e177Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Marcos-Fosch C. Cabezas J. Crespo J. Buti M. Anti-epileptic drugs and hepatitis C therapy: real-world experience.J Hepatol. 2021; 75: 984-985Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 5Natali K.M. Jimenez H.R. Slim J. When coadministration cannot be avoided: real world experience of direct acting antivirals for the treatment of hepatitis C virus infection in patients on first generation anticonvulsants.J Pharm Pract. 2022; 35: 495-499Crossref PubMed Scopus (4) Google Scholar We present additional data in the hopes of guiding clinicians when encountering these situations in the real-world setting. We present data on five treatment-naïve patients with chronic HCV. Two patients were infected with genotype 1 and three with genotype 3 HCV. All patients had F2 fibrosis or less at baseline, and none were co-infected with HIV or hepatitis B virus. All patients were on concomitant AEDs for seizure disorder; four on carbamazepine, oxcarbazepine, or phenobarbital monotherapy and one on a combination of carbamazepine and phenytoin. No AED dosage adjustments were made prior to initiating and/or during HCV treatment with GLE/PIB or sofosbuvir/velpatasvir (SOF/VEL). We did not measure plasma levels during the course of treatment, which would have offered more insight into the relationship between DAA plasma levels and rates of SVR. Nonetheless, all patients achieved SVR without treatment-related adverse events. Furthermore, viral suppression was maintained 8 to 52 weeks post-SVR (Table 1).Table 1Patient characteristics.Patient 1Patient 2Patient 3Patient 4Patient 5SexMaleFemaleFemaleMaleMaleAge (years)6075706860Genotype/subtype3a1b1a3a3aPast treatment experienceNaïveNaïveNaïveNaïveNaïveFibrosis assessmentF0F1–F2F1F2F2AED + dose (mg)Carbamazepine 600 mg twice daily; phenytoin twice daily (200 mg/300 mg)Phenobarbital 75 mg dailyOxcarbazepine 600 mg twice dailyCarbamazepine 600 mg twice dailyCarbamazepine 400 mg twice dailyTreatment regimen + duration (weeks)GLE/PIB × 12 weeksGLE/PIB × 12 weeksGLE/PIB × 8 weeksGLE/PIB × 8 weeksSOF/VEL × 12 weeksBaseline HCV RNA (IU/ml)9,4301,567,0027,940,0002,500,80017,100,000End of treatment HCV RNA (IU/ml)<15<15<15<15<1512 weeks post- treatment (SVR) HCV RNA (IU/ml)<15<15<15<15<15Weeks post-SVR; HCV RNA (IU/ml)8 weeks; <1528 weeks; <1528 weeks; <1552 weeks; <1552 weeks; <15AED, anti-epileptic drug; GLE/PIB, glecaprevir/pibrentasvir; HCV, hepatitis C virus; SOF/VEL, sofosbuvir/velpatasvir; SVR, sustained virologic response. Open table in a new tab AED, anti-epileptic drug; GLE/PIB, glecaprevir/pibrentasvir; HCV, hepatitis C virus; SOF/VEL, sofosbuvir/velpatasvir; SVR, sustained virologic response. Previous reports described two patients with genotype 3 HCV while we present data on three additional patients, all of whom achieved SVR. It is important to note, SVR was achieved in the absence of other interacting medications and/or cirrhosis, which is associated with lower SVR rates in those with genotype 3 HCV. Additionally, carbamazepine, oxcarbazepine, phenobarbital, and phenytoin all undergo some degree of hepatic metabolism. In the setting of cirrhosis, this may lead to alterations in AED metabolism, and in some cases, higher AED concentrations. Considering these factors, there is insufficient data to support the concomitant use of DAAs and AEDs in patients with cirrhosis, with or without genotype 3 HCV. Thus, further research is needed to determine if extended DAA treatment durations and/or AED dosage reductions are warranted in this population. Moreover, patients with genotype 3 HCV were treated with 8 weeks of GLE/PIB or 12 weeks of SOF/VEL with the exception of one patient who received a longer course of GLE/PIB than indicated (12 weeks). However, this same patient was taking combination AED therapy with carbamazepine and phenytoin. In the absence of cirrhosis, HCV treatment with 8 weeks of GLE/PIB or 12 weeks of SOF/VEL appears to be suitable for patients on AED monotherapy. Lastly, we measured HCV RNA levels post-SVR to ensure continued viral suppression. SVR 12 weeks after the end of treatment (SVR12) has been adopted as the efficacy endpoint for DAAs, but its definition is rather arbitrary. Though relapse occurs in <1% of patients who achieve SVR12, patients on concomitant interacting AEDs were not studied.[6]Burgess S.V. Hussaini T. Yoshida E.M. Concordance of sustained virological response at weeks 4, 12 and 24 post-treatment of hepatitis C in the era of new oral direct-acting antivirals: a concise review.Ann Hepatol. 2016; 15: 154-159PubMed Google Scholar HCV RNA levels were checked 8, 28, and 52 weeks post-SVR12 in one, two, and two patients, respectively, and they remained undetectable. This is reassuring as it implies additional monitoring, i.e. HCV RNA levels post-SVR, may not be necessary, and SVR12 remains an appropriate outcome measure of efficacy. In summary, reductions in DAA concentrations with concomitant use of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin have not been shown to be clinically significant in real-world settings. In the absence of cirrhosis, if the risk of discontinuing or substituting these AEDs is high, clinicians may consider continuing them when initiating DAAs, without the need for dose adjustments, drug exposure testing, or post-SVR viral suppression monitoring. The creation of this manuscript was not funded. SP serves on the speaker bureau for AbbVie and Gilead and has served on their advisory board. AM serves on the speaker bureau for AbbVie and has served on the advisory board for AbbVie and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details. SP led the study concept and design. SP, AM, and HD equally contributed to acquisition of data, analysis, and interpretation of data. SP led initial drafting of the manuscript, and AM and HD edited the manuscript. All authors reviewed the manuscript for important intellectual content, gave final approval of data, and are accountable for the work. The following are the supplementary data to this article: Download .pdf (.25 MB) Help with pdf files Multimedia component 1